1. Technical Field
The present invention is related generally to fredericamycin A. More particularly, the present invention is related to new, water soluble, biologically active derivatives of fredericamycin A and a process for making the same.
2. State of the Art
In 1980 Pandey et al (J. Antibiotics, 34:1389, 1981) reported the isolation and physicochemical properties of a new antitumor antibiotic, fredericamycin A (FCRC-A48, NSC-305263) from a soil isolate of Streptomyces griseus (FCRC-48). Based on its ultraviolet-visible spectrum, infra red spectrum, proton and carbon-13 nuclear magnetic resonance spectra and mass spectrum, it was judged to be a novel acid-base indicator type of compound. Among various properties, it was found that fredericamycin A had no activity against Gram-negative bacteria but showed good activity against Gram-positive bacteria and fungi. Furthermore, fredericamycin A was found very cytotoxic. Its ED.sub.50 against mouse leukemias P388 and L1210 compared closely to the reported values for actinomycin D and adriamycin (Warnick-Pickle et al. J. Antibiotics, 34:1402, 1981).
In vivo studies indicated that fredericamycin A was effective in extending the life span of mice inoculated with P388 leukemic cells and in reducing the median tumor weight of the CD8F mouse mammary tumor. However, it was ineffective against L1210 leukemia, Lewis lung carcinoma, C38 colon tumor, MX-1 breast xenograft, and LX-1 lung xenograft. It showed marginal activity against B.sub.16 melanoma. Due to poor solubility, further toxicological and pharmacological studies could not be carried out to broaden the utility and range of activity of fredericamycin A.
A number of reports have appeared on the isolation, biological activity, structure and biosynthetic studies of fredericamycin A (Misra et al. J. Am. Chem. Soc. 104:4478, 1982; Byrne et al., 1982 "Biosynthesis of Fredericamycin, A New Antitumor Antibiotic", 22nd Interscience Conference on Antimicrobial Agents and Chemotherapy; Byrne et al., 1985, Biochem. 24:478). However, no mention is made in any of these reports of water soluble derivatives, though a recent publication describes the acetyl, lauroyl and hydrogenated acetyl derivatives (Koichi et al., 1985, Chem. Abst. 103, 104798C, and Koichi et al 1986, Chem. Abstr. 104:33948J). Although these reported derivatives have slightly better solubility in organic solvents, their biological activity is reduced to a great extent compared to fredericamycin A. More importantly, these derivatives are not water soluble which, of course, is an important consideration for preparing formulations and toxicological studies.